Inflammation, a key component of the immune system, functions in both defense and pathophysiological events to maintain the homeostasis of tissues, organs and individual cells. Inflammation can be classified as either acute or chronic. Acute inflammation is a short-term process characterized by the classic signs of inflammation, i.e. swelling, redness, pain, heat, and loss of function, due to infiltration of tissues by plasma and leukocytes. It occurs as long as the injurious stimulus is present and ceases once the stimulus has been removed. Chronic inflammation is a pathological condition characterized by concurrent active inflammation, tissue destruction, and attempts at repair. Chronically inflamed tissue is characterized by the infiltration of mononuclear immune cells (monocytes, macrophages, lymphocytes, and plasma cells), tissue destruction, and attempts at healing, which include angiogenesis and fibrosis.
Without inflammation, wounds and infections would not be able to heal and progressive destruction of the tissue would threaten the survival of the organism. Unchecked inflammation, on the other hand, can lead to a host of diseases, such as hay fever, atherosclerosis and other cardiovascular diseases, neurodegenerative diseases such as Alzheimer's, cancer and rheumatoid arthritis. For these reasons, inflammation is tightly regulated by the body.
Inflammation is controlled by more than 400 genes. The pro-inflammatory genotype, which appears dominant, increases our vulnerability to, and intensity of, inflammatory reactions, which underlie chronic inflammatory diseases, especially in old age. (Ferencik et al., Inflammation—a lifelong companion. Folia Microbiol (Praha). 2007; 52:159-73). Although joint diseases have long been the prototypical inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, autoimmune diseases, and cancer are now appreciated as having inflammation as a unifying component of their pathogenesis.
Alzheimer's disease (AD) includes inflammatory processes in the senile plaques and surrounding glia, with increased expression of acute phase proteins such as C-reactive protein (CRP) and IL-6. Increased IL-6 expression during normal brain aging suggests a link of age-related inflammation to the onset of AD during aging. Blood levels of CRP and IL-6 are also associated with higher risk of Alzheimer's disease and cognitive decline during aging (Finch and Morgan, Systemic inflammation, infection, ApoE alleles, and Alzheimer disease: a position paper. Curr Alzheimer Res. 2007; 4:185-9).
Inflammation plays a crucial role in all steps characterizing the atherosclerotic process. Circulating CRP (C-reactive protein) levels have emerged as a powerful independent determinant of cardiovascular events. Hypertension is closely linked to inflammation. Experimental data and results from cross-sectional studies in humans strongly support this notion (Virdis et al., C-reactive protein and hypertension: is there a causal relationship? Curr Pharm Des. 2007; 13:1693-8). In cancer, chronic inflammation often acts as a tumor promoter, resulting in aggressive cancerous growth and spread. Many of the same inflammatory factors that promote tumor growth also are responsible for cancer cachexia/anorexia, pain, debilitation, and shortened survival. A compelling case has been made even for attacking inflammation at initial diagnosis to improving patient quality of life and survival. Serum levels of CRP correlate with poor prognosis in cancer patients (MacDonald N. Cancer cachexia and targeting chronic inflammation: a unified approach to cancer treatment and palliative/supportive care. J Support Oncol. 2007; 5:157-62).
Nonsteroidal anti-inflammatory drugs (NSAIDS) are the most widely used anti-inflammatory compounds, with aspirin, the prototypical NSAID, still being one of the oldest and most extensively used medication in the world (Stanley P, Hegedus R. Aspirin—the first hundred years. Biologist (London) 2000; 47:269-71; Rinsema T J. One hundred years of aspirin. Med Hist 1999; 43:502-7). NSAIDs have a significant antineoplastic effect, which should be viewed, at least in part, in the context of the increasingly appreciated role of inflammation in cancer. Aspirin is formally documented to be a chemopreventive agent against colon cancer [3,4]. For other NSAIDS, the evidence on their antineoplastic properties is quite strong but still it is based mainly on epidemiological studies (Baron J A. What now for aspirin and cancer prevention? J Natl Cancer Inst 2004; 96:4-5; Jacobs E J, Rodriguez C, Mondul A M, Connell C J, Henley S J, Calle E E, et al. A large cohort study of aspirin and other nonsteroidal anti-inflammatory drugs and prostate cancer incidence. J Natl Cancer Inst 2005; 97:975-80; Thun M J, Henley S J, Gansler T Inflammation and cancer: an epidemiological perspective. Novartis Foundation symposium 2004; 256:6-21; discussion 2-8, 49-52, 266-9). For example, a recent meta-analysis of 91 epidemiological studies showed a significant exponential decline with increasing intake of NSAIDs in the risk for 7-10 malignancies including the four major types: colon, breast, lung, and prostate cancer (Harris R E, Beebe-Donk J, Doss H, Burr Doss D. Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of non-selective COX-2 blockade (review). Oncology reports 2005; 13:559-83; Ratliff T L. Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of non-selective COX-2 blockade (review). The Journal of urology 2005; 174:787-8).
NSAIDs prevent cancer likely through pleiotropic effects (reviewed in Rayyan Y, Williams J, Rigas B. The role of NSAIDs in the prevention of colon cancer. Cancer Invest 2002; 20:1002-11; Shiff S J, Rigas B. Aspirin for cancer. Nat Med 1999; 5:1348-9.). It is, however, clear that conventional NSAIDs do not meet two important criteria for their wide application as chemopreventive agents against cancer, i.e. safety and high efficacy, as NSAIDs are associated with a considerable number of side effects, and their efficacy is rather limited, not exceeding 50% (Rayyan Y, Williams J, Rigas B. The role of NSAIDs in the prevention of colon cancer. Cancer Invest 2002; 20:1002-11). Thus there is a need to develop compounds with improved efficacy and safety profiles for the treatment of various diseases related to inflammation.